PROJECT SUMMARY/ABSTRACT Sepsis remains one of the leading cause of mortality in intensive care unit (ICU) and represents a significant economic burden in the USA, which has been estimated $16.7 billion per year for the health care of patients with sepsis. Thus, there is an urgent medical need for the development of effective therapies for sepsis. Depression of thyroid function is often observed in patients with sepsis, which is characterized by decreased blood total triiodothyronine (T3) and free T3. Although thyroid dysfunction seems to be associated with a worse prognosis, it is still unclear whether this alteration is a protective adaption or maladaptive response. To date, the beneficial effect of replacing thyroid hormone (TH) on outcome in patients with sepsis is still controversial. Macrophages play a key role in the innate immunity and host defense, forming the first line of defense against bacterial infection. Currently, accumulating data show that TH can significantly affect the function of the immune system and exert responses in various immune cells, including dendritic cells, lymphocytes, and more importantly, macrophages. Exosomes (EXOs) are endogenously generated by host cells and may serve as ?nature's delivery system?. Drug encapsulation has recently been investigated and several loading approaches have been reported. However, there are numerous questions to be addressed before knowledge-based delivery strategies can be developed. Hypothesis: TH delivery using EXOs will efficiently target macrophages in the body and not trigger significant adverse effects based on our recent discoveries. Our ultimate goal is to test whether EXOs-mediated TH delivery could provide protective effects against by controlling the immune response in macrophages. To achieve these goals, we will pursue the following complementary Specific Aims: Specific Aim I: To investigate the application of EXOs as TH delivery vehicle. Specific Aim II: To explore the therapeutic potential of EXOs-mediated T3 replacement against sepsis. Significance: Our proposed study will investigate the biodistribution of EXOs given via tail vein injection at both tissue and the cellular levels. If we demonstrate that EXOs could serve as a drug carrier that efficiently targets macrophages in vivo, therapies using EXOs might be advanced into clinical trials against infectious diseases in human. Besides, in this proposal, we aim to employ EXOs as a carrier of T3 molecules and elucidate the fundamental questions, including the characters of EXOs and the capacity to transport functional T3 molecules. These studies may identify EXOs-mediated TH replacement as a potential new therapeutic strategy for sepsis without adverse effects. Collectively, successful completion of the proposed aims might lead to better outcomes in ICU patients with severe sepsis in the future.